Prognostic significance of germline BRCA mutations in patients with HER2-POSITIVE breast cancer.

Background: HER2-positive breast cancers are rare amongst BRCA mutation carriers. No data exist regarding clinicopathological characteristics and prognosis of this subgroup of patients. Materials and methods: Using a retrospective matched cohort design, we collected data from 700 women who were diagnosed with operable invasive breast cancer from January 2006 to December 2016 and were screened for germline BRCA mutations. Clinicopathological features and survival rates were analyzed by BRCA and HER2 status. Results: One hundred and fifteen HER2-positive/BRCA mutated cases were evaluated in comparison to the three control groups: HER2-positive/BRCA wild type (n = 129), HER2-negative/BRCA mutated (n = 222), HER2-negative/BRCA wild type (n = 234). HER2-positive breast cancers were more likely to have high histologic grade and high proliferation rate than HER2-negative neoplasms, regardless of BRCA mutation status. An interaction between BRCA mutations and HER2-positive status was found to correlate with worse survival after adjusting for prognostic variables (HR = 3.4; 95% CI: 1.3-16.7). Conclusions: Co-occurrence of BRCA mutations and HER2-positive status is a poor prognostic factor in patients with early or locally advanced breast cancer. This finding may be a proof of concept that a combined pharmacological intervention directed to these targets could be synergistic

Efficacy and safety of neoadjuvant chemotherapy plus trastuzumab and pertuzumab in non-metastatic HER2-positive breast cancer in real life: NEOPEARL study.

Background In HER2+ breast cancer (BC) patients (pts) the pathological complete response (pCR) is associated with improved survival. With regimens based on the combination of trastuzumab (T), pertuzumab (P) and chemotherapy, pCR rates are slightly over 48%. We conducted a retrospective analysis on HER2+ BC pts to describe the outcomes of neoadjuvant combination of P+T and chemotherapy in the real-life setting. Methods Our cohort included 64 pts treated between Sept 2015 and Mar 2018 in 15 Italian Cancer Centers. Treatment outcomes were analyzed in terms of pCR (defined as ypT0/Tis, ypN0i-) and toxicities, recorded according to National Cancer Institute Common Toxicity Criteria. Statistical analysis was performed with T di Student test and χ2 test. Results Overall, in the 55 evaluable pts median age was 50 (range 28-77) and 29 pts (53%) were pre-menopausal. 24 pts (45%) were ER-/PgR-, 12 (21%) ER+/PgR-, 16 (29%) ER+/PgR+, median ki67 was 40. 9% of pts were cT1, 73% cT2, 13% cT3 and 5% cT4; 42 pts (76%) were cN+. All pts received 4 cycles of T (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) and P (loading dose 840 mg, followed by 420 mg every 3 weeks). In 42 pts T+P were administered with docetaxel (75 mg/mq every 3 weeks), in 8 pts with paclitaxel (80 mg/mq) and 5 pts received docetaxel and carboplatin (AUC5). In 13 pts also 3 cycles of anthracyclines, according to the FEC scheme, were administered. A pCR was achieved in 29 pts (53%). No significant associations were found between pCR and baseline characteristics or treatments schedule. Seven out of 55 (13%) pts reported G3-G4 toxicities (5 pts neutropenia G3-G4, 1 pt vomiting G3, 1 pt diarrhoea G3, 1 pt anemia G3). Three out of 4 pts treated with docetaxel, carboplatin and P+T reported G3/G4 toxicities. A significant association was found between chemotherapy schedule and toxicities (p = 0.004). Conclusions The association of P+T+chemotherapy improved pCR rate in HER2+ BC pts treated in the real-life setting. Our results showed that the selection of chemotherapy that will be associated with the dual blockade of HER2 is of paramount importance in order to avoid severe toxicities and increase the compliance with treatment

Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting

We analyzed data from 738 HER2\u2010positive metastatic breast cancer (mbc) patients treated with pertuzumab\u2010based regimens and/or T\u2010DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression free survival at first\u2010line (mPFS1) was 12 months. Pertuzumab as first\u2010line conferred longer mPFS1 compared to other first\u2010line treatments (16 vs 9 months, p=0.0001), regardless of IHC subtype. Median PFS in second\u2010line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T\u2010DM1 compared to other agents (7 vs 6 months, p=0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs) (p=0.17), while a trend emerged for tumors with one HR (p=0.05). Conversely, PFS2 gain was significant in HRs\u2010negative tumors (p=0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T\u2010DM1 in second\u2010line following pertuzumab were significantly lower compared to pertuzumab\u2010na\uefve patients(p=0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p=0.02 and p=0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment\u2010related outcomes of HER2\u2010positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor (ER) pathways in HER2\u2010positive (mbc) patients

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real- world experience

We addressed trastuzumab emtansine (T-DM1) e cacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab- pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing signi cant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical bene t 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no di erences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab- pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab- pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival bene t (p<0.0001), while overall survival was positively a ected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical bene t (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to con rm and interpret our data on apparently lower T-DM1 e cacy when given as second-line treatment after pertuzumab, and on the optimal sequence order

Clients

Il lavoro rappresenta un aggiornamento arricchito e ampliato negli argomenti di un lavoro realizzato dal curatore nel 1996. In esso si ritrova una combinazione ottimale di aspetti inerenti un'accurata ricognizione della letteratura sui principali temi di management del comparto in esame oltre a una raccolta di dati e ricognizione di case histories provenienti dai differenti contesto di mercato. La pubblicazione di fatto ha uno spettro europeo

Pneumonitis and pulmonary fibrosis associated with breast cancer treatments

To review the available published data regarding the incidence, mechanisms of pathogenesis, clinical presentations and management of pneumonitis caused by anti-cancer treatments (radiotherapy (RT) and systemic agents) that are included in the guidelines of the treatment of breast cancer (BC) and address the issues on the current grading classification of pneumonitis. A literature search was performed between July and October 2013 using PubMed for papers published from January 1989 to October 2013. Any clinical trial, case report, case series, meta-analysis or systematic review that reported on pulmonary toxicity of any BC therapeutic modality was included (only papers published in English). Most of anticancer treatments currently used in the management of BC may induce some degree of pneumonitis that is estimated to have an incidence of 1-3 %. There is an obvious distinction between chemotherapy- and targeted treatment-related lung toxicity. Moreover, the current classification of pneumonitis needs to be modified as there is a clear diversity in grade 2. As pneumonitis is relatively common and reported as side effect of new anticancer agents, physicians need to be aware of the clinical and radiological manifestations of drug- and RT-induced toxicities in patients with BC. A key recommendation is the subdivision of grade 2 cases to two subgroups. We provide an algorithm, along with real life cases as managed in the breast Unit of Royal Marsden Hospital, with the aim to guide physicians in managing all possible eventualities that may come across in clinical practise